HIV 1 is not only a lymphotropic but also neurotropic virus. The major target cell of the virus in the brain is the microglia, a cell of the monocyte-macrophage (MM) lineage which resides in the nervous system. We have investigated the role of the env gene in HIV neurotropism using chimeric viruses containing portions of neurotropic and lymphotropic viral genomes. We find that a region of gpl2O glycoprotein upstream of the CD4 binding site and comprising the V3 loop is essential to allow efficient entry into microglial cells. Moreover the same molecular determinants appear to control neurotropism and MM tropism. We will now analyze the specific determinants which might give a "neurotropic" signature to particular HIV- 1 strains by examining directly DNA isolated from brain at autopsy of AIDS patients with psychomotor dysfunction. We will determine whether these variants are present in the mononucleated circulating white cells early in the disease. The restricted nature of HIV-1 neurotropism is expressed at the cellular level. When astrocytes and oligodendrocytes enriched cultures are prepared from adult human brain and deprived of microglia, no evidence of viral entry and/or replication in these cells has yet been found. Ongoing studies will explore whether galactocerebroside expressing oligodendrocytes in human brain primary cultures can allow HIV 1 entry as described in transformed cell lines.